Mechanistic Evaluations of Pre-Cessation Therapies for Smoking Cessation

Inclusion Criteria: * Are generally healthy; * Are 18-50 years old; * Smoke an average of at least 10 cigarettes per day for at least three cumulative years; * Have an afternoon expired air carbon monoxide (CO) reading of at least 10ppm; * Are right-handed as measured by a two-item scale used in our laboratory; * Express a desire to quit smoking in the next thirty days. * Potential subjects must agree to use acceptable contraception during their participation in this study. Potential subjects must agree to avoid the following during their participation in this study: * participation in any other nicotine-related modification strategy outside of this protocol; * use of tobacco products other than cigarettes, including pipe tobacco, cigars, e-cigarettes, snuff, and chewing tobacco; * use of experimental (investigational) drugs or devices; * use of illegal drugs; * use of opiate medications. Exclusion Criteria: * Inability to attend all required experimental sessions; * Presence of conditions that would make MRI unsafe (e.g. pacemaker); * Hypertension (systolic \>140 mm Hg, diastolic \>100 mm Hg, coupled with a history of hypertension); subjects with no previous diagnosis of hypertension may have a screening blood pressure up to 160/100. * Hypotension with symptoms (systolic \<90 mm Hg, diastolic \<60 mm Hg). * Coronary heart disease; * Lifetime history of heart attack; * Cardiac rhythm disorder (irregular heart rhythm); * Chest pains (unless history, exam, and ECG clearly indicate a non-cardiac source); * Cardiac (heart) disorder (including but not limited to valvular heart disease, heart murmur, heart failure); * History of skin allergy; * Active skin disorder (e.g., psoriasis) within the last five years, except minor skin conditions (including but not limited to facial acne, minor localized infections, and superficial minor wounds); * Liver or kidney disorder (except kidney stones, gallstones); * Gastrointestinal problems or disease other than gastroesophageal reflux or heartburn; * Active ulcers in the past 30 days; * Lung disorder (including but not limited to Chronic obstructive pulmonary disease (COPD), emphysema, and asthma); * Brain abnormality (including but not limited to stroke, brain tumor, and seizure disorder); * Migraine headaches that occur more frequently than once per week; * Recent, unexplained fainting spells; * Problems giving blood samples; * Diabetes; * Current cancer or treatment for cancer in the past six months (except basal or squamous cell skin cancer); * Other major medical condition; * Current psychiatric disease (with the exception of anxiety disorders, Obsessive-compulsive disorder (OCD) and Attention deficit hyperactivity disorder (ADHD)); * Bulimia or anorexia; * Suicidal ideation (within the past 10 years) or lifetime occurrence of attempted suicide; * Current depression; * Pregnant or nursing mothers; * Alcohol abuse; * Significant adverse reaction to nicotine patch, bupropion/Wellbutrin/Zyban or Chantix/Varenicline in the past. * Use (within the past 30 days) of: * Illegal drugs (or if the urine drug screen is positive); * Experimental (investigational) drugs; * Psychiatric medications including antidepressants, anti-psychotics or any other medications that are known to affect smoking cessation (e.g. clonidine); * Smokeless tobacco (chewing tobacco, snuff), cigars or pipes; * Nicotine replacement therapy or any other smoking cessation aid. * Use (within the past 14 days) of: * Opiate medications for pain or sleep (non-opiate medication for pain or sleep will be allowed).